Sodium Carbonate → 3-bromo-5-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-amine

HRID 596031Notes

Reaction equation

HRID 596031 reaction equation
[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)[CH2:11][C@@H:10]1[F:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].CC(OC)(C)C>CS(C)=O.O>[Br:30][C:17]1[C:18]([NH2:21])=[N:19][CH:20]=[C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@@H:10]([F:22])[CH2:11]2)[N:16]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 15413tert-Butyl methyl etherHCID 67184N-bromobutanimideHCID 1232789255-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-amine

Product 1

HCID 1233646413-bromo-5-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-amineYield 100%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
35 °C

Procedure

A solution of 5-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-amine (620.0 g, 1904.8 mmol) in DMSO (5 L) and water (400 mL) was cooled to ˜4° C. NBS (389.8 g, 2190.5 mmol) was added in 10 portions within 1 hour and the reaction temperature was controlled under 5° C. with continuous stirring for 30 minutes. After addition of 0.3 M aqueous Na2CO3 (8.5 kg), the reaction temperature was increased to 35° C. MTBE (4.5 kg) was added and the mixture was stirred for a further 10 minutes. After phase separation, the aqueous layer was extracted with MTBE (4 kg). The combined organic layers were washed successively with 0.3 M aqueous Na2CO3 (8.5 kg) and water (8 kg), and concentrated under vacuum at 30-40° C. to give crude product 3-bromo-5-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-amine as a foam (770 g). This crude product was used in next step without further purification. ESI-MS (m/z): 404.1105, 406.1093 ([M+H]+, 100). HPLC (method A), retention time=14.38 min. 1H NMR (400 MHz, CDCl3): 7.81 (s, 1H), 4.99 (br. s, 2H), 4.37-4.42, 4.25-4.30 (m, 1H), 3.66-3.72 (m, 1H), 2.67-2.73 (m, 1H), 2.26-2.29 (m, 1H), 1.97-2.02 (m, 1H), 1.74-1.87 (m, 2H), 1.44-1.63 (m, 2H), 0.91 (s, 9H), 0.10 (d, J=8 Hz, 6H).

Workup

  1. customwas controlled under 5° C.
  2. stirringthe mixture was stirred for a further 10 minutes
  3. customAfter phase separation
  4. extractionthe aqueous layer was extracted with MTBE (4 kg)
  5. washThe combined organic layers were washed successively with 0.3 M aqueous Na2CO3 (8.5 kg) and water (8 kg)
  6. concentrationconcentrated under vacuum at 30-40° C.

Sources & evidence

ORD record
ord-9cafa4f177b64dc6928c6827178e855d
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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